Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

Haroula Kontaki; Marina Koukaki; Maria Vasilarou; Antonis Giakountis; Elena Deligianni; Xiaolin Luo; Youngsoo Kim; Iannis Talianidis

doi:10.1016/j.isci.2021.102473

Targeting Smyd3 by next-generation antisense oligonucleotides suppresses liver tumor growth

iScience. 2021 Apr 24;24(5):102473. doi: 10.1016/j.isci.2021.102473. eCollection 2021 May 21.

Authors

Haroula Kontaki¹, Marina Koukaki¹, Maria Vasilarou^{1

2}, Antonis Giakountis³, Elena Deligianni¹, Xiaolin Luo⁴, Youngsoo Kim⁴, Iannis Talianidis¹

Affiliations

¹ Institute of Molecular Biology and Biotechnology, FORTH, 70013 Herakleion, Crete, Greece.
² Department of Biology, University of Crete, 70013 Herakleion, Crete, Greece.
³ Department of Biochemistry and Biotechnology, University of Thessaly, Larissa 41500, Greece.
⁴ Ionis Pharmaceuticals, Carlsbad, CA, USA.

Abstract

The oncogenic function of suppressor of variegation, enhancer of zeste and MYeloid-Nervy-DEAF1-domain family methyltransferase Smyd3 has been implicated in various malignancies, including hepatocellular carcinoma (HCC). Here, we show that targeting Smyd3 by next-generation antisense oligonucleotides (Smyd3-ASO) is an efficient approach to modulate its mRNA levels in vivo and to halt the growth of already initiated liver tumors. Smyd3-ASO treatment dramatically decreased tumor burden in a mouse model of chemically induced HCC and negatively affected the growth rates, migration, oncosphere formation, and xenograft growth capacity of a panel of human hepatic cancer cell lines. Smyd3-ASOs prevented the activation of oncofetal genes and the development of cancer-specific gene expression program. The results point to a mechanism by which Smyd3-ASO treatment blocks cellular de-differentiation, a hallmark feature of HCC development, and, as a result, it inhibits the expansion of hepatic cancer stem cells, a population that has been presumed to resist chemotherapy.

Keywords: Cancer; Epigenetics.